The objective of the proposed Drug Abuse Research Center is to determine the extent and magnitude of the effects of narcotics on brain biochemistry and ultrastructure during the development of tolerance and physical dependence. The specific goal of the proposed research is to lay a foundation of basic information on the neurochemical and morphological effects of the narcotics from which studies of the actual "mechanisms" involved in tolerance and dependence can logically progress. We shall use a variety of micro-analytic chemical and immunochemical techniques, radioassays and quantitative-histochemistry to determine the effects of narcotics on: 1) The biogenic amines; 2) Brain protein synthesis; 3) Brain metabolism; 4) Representative cerebral enzymes; 5) Brain morphology and ultrastructure; and 6) Additional studies will be conducted to examine the neuroanatomical correlates of tolerance to and dependence on narcotics. Our approach will be highly integrated and interdisciplinary and we shall correlate, whenever possible, pharmacologic, biochemical and morphological observations within a given region of brain during various phases of morphine treatment and subsequent withdrawal. All of these determinations will be made in histologically well-defined regions of brain, including the major nuclei of the hypothalamus, thalamus, caudate, midbrain, medulla, cerebellum and cerebral cortex.